GRANT=P50MH58911-06-0004 Stress experiences can precipitate psychiatric illnesses, including depression and post-traumatic stress disorder. Stress includes anxiety and fear, for which the amygdala is a key brain region, and the hypothalamo-pituitary-adrenal (HPA) axis plays an important role in mediating the effects of stress both on the brain and the rest of the body via the ability of glucocorticoids to regulate gene expression and lead to downstream effects that interact with other mediators, such as excitatory amino acid neurotransmitters. We have found that acute and chronic stress increases fear and anxiety and we propose that they do so, at least in part, by stress-induced structural plasticity (dendritic remodeling, spine synapse formation and suppression of neurogenesis) that we have found in hippocampus. We have found that stress also cause structural plasticity (dendritic remodeling, spine synapse formation) in amygdala and prefrontal cortex. In collaboration with Proj 1 and 3 and the Imaging Core, we intend to study the interactions between these brain areas in regulating structural plasticity because the amygdala communications with these and other brain areas and together they mediate the complex effects on unlearned fear, fear conditioning, reconsolidation and extinction that are the topic of Proj.1. Project.4 examines stress-induced structural plasticity at the cellular and molecular levels using quantitative morphological methods with the Imaging Core and techniques such as in situ hybridization, immunocytochemistry and stereotaxic delivery of agents into the amygdala. These include viral vectors for delivering genes to specific brain regions. Some of the effects of acute and chronic stress in animal models differ between males and females, at least in part because of the actions of gonadal hormones in adult life and also during development. As a result, aspects of these gender differences will also be investigated in collaboration with all of the other projects. In collaboration with Proj.2, we will endeavor to translate these findings to the human brain, because long lasting changes in activity and structure of the amygdala, hippocampus and prefrontal cortex have been found in human depressive illness and anxiety disorders.